P378: CHEMO-FREE TREATMENT OF VAF INDUCE A EARLY AND DEEP MOLECULAR RESPONSEIN IN PATIENTS WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LEUKEMIA: A PROSPECTIVE, SINGLE ARM, PHASE II STUDY
Authors: Mengyun LI, Qingya Cui, Huiying Qiu, Lingling Liu, Zheng LI, Sifan Chen, Yan Yu, Jiannong Cen, Hongjie Shen, Jinlan Pan, Mingqing Zhu, Xiaming Zhu, Ying Wang, Suning Chen, Depei Wu, Xiaowen Tang
Journal: HemaSphere (2023)

Background: The 3-month complete molecular response(CMR) is a favourable prognostic factor for overall survival(OS), even negating the need for allogeneic haematopoietic stem cell transplant (allo-HSCT). The overall 3-month CMR of standard chemotherapy with TKIs is 57%. Preclinical data have suggested Bcl-2 inhibitors strongly induce apoptosis in Ph+ cells, and highly synergistic with TKIs, identifying BCL2 as a new therapeutic target of particular relevance in Ph+ ALL. Aims: We evaluated the efficacy and safety of a chemo-free combination of venetoclax, azacitidine and flumatinib (VAF) in patients with ND Ph+AL and accelerated or blast phase chronic myeloid leukemia(CML). The primary endpoint was CMR rate at end of two cycles of VAF. Secondary endpoints included relapse-free survival(RFS), overall survival(OS), and safety. Methods: We designed a single-arm phase 2 study in adults with ND Ph+ AL and CML-AP/BP. Patients received two cycles of VAF induction. Administration of the VAF regimen was as follows: venetoclax,100 mg d1, 200 mg d2,400 mg d3-21, orally; azacitidine,75 mg/m2, d1-7, subcutaneously; flumatinib, 600 mg once daily continuously from d4. Once patients reached CMR after two cycles of VAF induction, they received one cycle of high-dose cytarabine based-regime consolidation and proceed to allo-HSCT if eligible. VAF were repeated for patients ineligible for allo-HSCT every 4 weeks as maintenance therapy until disease progression. Twelve doses of prophylactic intrathecal chemotherapy were administered. Results: Between May 2022 and February 2023, a total of 20 ND patients were enrolled (14 Ph+ALL, 2 Ph+ B/M mixed phenotype acute leukemia(MPAL) and 4 CML-AP/BP). As of 28 February 2023, 13 patients had received two cycles of the VAF regimen (include 11 Ph+ ALL, 1 Ph+ B/M MPAL and 1 CML-BP), and 12 of them were evaluable for the primary endpoint (except for one with Ph+ ALL withdrew from this trial after discontinuing cycle2 due to severe COVID‐19 pneumonia). Patient characteristics and outcomes of VAF are summarised in table 1. After one cycle of VAF, CR/CRi rate was 100% (13/13). Of the 13 patients, 92.3% had a molecular response with 76.9% CMR and 15.4% MMR, and another one achieved a CCyR. The CMR rate at end of two cycles of VAF, the primary endpoint, increased to 83.3%. The median time from induction to CMR was 21d (range, 14-70d). No early death within 4 weeks was observed. The median duration of follow-up was 7.6 (3-9) months. The 6-month RFS and OS of all 12 patients was both 100%. The treatment was well-tolerated, the most common adverse hematological events reported were febrile neutropenia (grade 1-2,3 [23%] of 13). The median recovery time of neutropenia and thrombocytopenia was 11 and 5 days, respectively. The median number of red blood cell and platelet infusions were 5U and 15U. Mild non-hematological toxicities were reported. The average time of hospitalization was 22 days and 7 days of cycle1 and cycle2, respectively. All patients received cycle2 treatment in Day Ward. No patient discontinued due to toxicity. Summary/Conclusion: VAF is a highly effective and safe strategy to achieve early and deep molecular response in patients with ND Ph+AL in the frontline setting, providing a potential Day ward/Out-patient treatment strategyfor Ph+AL.Keywords: Philadelphia chromosome, Azacitidine, Venetoclax, Acute lymphoblastic leukemia